PROJECT SUMMARY/ABSTRACT The principal focus of this proposed project is cerebral microhemorrhage, the pathological substrate of cerebral microbleeds and the major hemorrhagic component of microvascular cerebrovascular disease. Our objective is to identify mechanisms that impact development of cerebral microbleeds in hypertension, the most common risk factor for microbleeds. The project investigators are a unique group of researchers with expertise in stroke neurology, vascular neurobiology, bioengineering, and biostatistics. We specifically propose the following aims and related hypotheses: Specific Aim 1: To determine the effects of hypertension on development of cerebral microhemorrhage. Hypothesis 1A: Hypertension provokes development of cerebral microhemorrhage. Hypothesis 1B: Hypertension-provoked cerebral microhemorrhage occurs at the capillary level. Hypothesis 1C: Hypertension-impaired cerebral vasomotor reactivity mediates development of cerebral microhemorrhage. Specific Aim 2: To determine the effects of angiotensin II and microglial activation in hypertension-provoked cerebral microhemorrhage development. Hypothesis 2A: Angiotensin II-induced hypertension produces microglial activation. Hypothesis 2B: Microglial activation mediates cerebral microhemorrhage development in hypertension. The proposed studies are designed as a series of synergistic in vivo studies to provide novel insights into microvascular brain disease. We will use a combination of studies of microvascular physiology and neuropathology to identify the vascular source of cerebral microbleeds. Our in vivo studies will address microbleed mechanisms, focusing on the roles of microglia and angiotensin II, including the angiotensin II type 1 receptor. Pharmacological inhibition of the latter (experiments using telmisartan) adds to the the translational significance of the project. This project directly addresses the highly prevalent problem of hemorrhagic microvascular disease of the brain. Our work and that of others have shown the near-ubiquitous presence of microhemorrhagic changes in aging human brain. Our multi-disciplinary team of investigators are uniquely capable of taking this project to completion, directly testing our microbleed conceptual models in the expectation that robust insights will emerge helping to transform the management of microvascular disorders of the brain which, along with Alzheimer?s disease, represents the most common cause of neurological morbidity of aging.